Low-dose interleukin-2 (IL-2) was found to be safe and well tolerated in a phase 1 and 2a trial of 12 patients with systemic lupus erythematosus (SLE). The treatment may be beneficial in reducing disease activity, researchers report in Sept. 1 issue of The Lancet Rheumatology.
Systemic lupus and other autoimmune conditions are thought to be associated with an IL-2 deficiency which can lead to fewer regulatory T cells which can become dysfunctional. So in this study, which was led by Jens Humrich, M.D., of the University Hospital Schleswig-Holstein in Germany, researchers sought to determine if low doses of IL-2 could safely and effectively restore regulatory T-cell homeostasis in patients with systemic lupus.
This study, which was a prospective, open-label uncontrolled study called PRO-IMMUN, included adult systemic lupus patients with moderate-to-severe disease activity despite previous treatments with at least two conventional therapies.
Participants received daily subcutaneous low-dose daily injections of recombinant human IL-2 (aldesleukin) through four cycles with increasing doses. The doses were given for five days followed by a nine to 16-day rest period.
The primary outcome was safety and a 100 percent increase in the proportion of specific regulatory T-cells at day 62 after four treatment cycles. Disease activity represented a secondary outcome. Eleven (92%) of the 12 patients achieved the primary endpoint .
In ten patients, SELENA-SLEDAI scores were lower at day 62 than at baseline, and no severe disease flares were observed during the treatment period. The decrease in disease activity was directly correlated the increase in regulatory T cells.
No serious adverse events occurred, but nearly half (47 percent) of the patients experienced mild to moderate adverse events, such as injection-site reaction.
“In this phase I and II-a study, we showed that provision of lowdose IL2 therapy is well tolerated and results in increased proportions of total regulatory T cells and of regulatory T cells expressing high levels of CD25 in patients with treatmentrefractory SLE,” the authors wrote.
Disease activity scores were lower at day 62 with no severe SLE flares during the study period. Larger increases in regulatory T-cell populations correlated with decreases in disease activity.
“Our findings are broadly in line with those of previous studies of regulatory Tcell responses to lowdose IL2 therapy in diverse immunological diseases, showing that lowdose IL2 therapy results in a potent induction of a regulatory Tcell response,” the authors wrote.
In an editorial response to the study, Daniel Wallace, M.D., of Cedars-Sinai in Los Angeles, agrees that this approach, while not new, has promise as a potential treatment for patients with systemic lupus. “Expansion of regulatory T cells while suppressing inflammation is an attractive approach to management of patients with SLE,” he wrote.
While IL-2 treatment raised regulatory T-cell numbers, this effect was transient which suggest that an induction phase followed by a maintenance phase of IL-2 administration may be preferable to cyclical treatment.
In addition to IL-2 representing a potential treatment for systemic lupus, the significant relationship between the increase in proportions of these specific regulatory T–cells may facilitate the monitoring efficacy of treatment in SLE through measuring T-cell levels as a biomarker for clinical responsiveness.
The results of these two trials are promising, however, the results should be confirmed in large placebo-controlled trials.
Dr. Wallace also points out in his commentary on the article that corticosteroids, rapamycin, and autologous T-cell infusions may also be useful for expanding regulatory T-cell populations in patients with SLE while at the same time suppressing inflammation leading to improvements in nephritis and other pathologic features of lupus.
Funding was provided by Bristol-Myers Squibb, ILTOO, and Roche for, Dr. Humrich, Boehringer-Ingelheim and Actelion for Dorte Huscher, GlaxoSmithKline and Amgen for Eugen Feist, and Amgen for Gerd-Rudiger Burmester.
Jens Y Humrich, Caroline von Spee-Mayer, Elise Siegert. Et al. “Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial.” Lancet Rheumatology, Volume 1, Issue 1, September 2019, Pages e44-e54
Daniel J Wallace. “Low-dose interleukin-2 for systemic lupus erythematosus?” The Lancet Rheumatology, Volume 1, Issue 1, September 2019, Pages e7-e8